The Spliceosome: A New Therapeutic Target in Chronic Myeloid Leukaemia

Area of Science:

• Molecular Biology
• Cancer Biology
• Hematology

Background:

• RNA splicing factors are frequently dysregulated in cancer, acting as oncogenes or tumor suppressors.
• Previous work indicated DNA methylation alterations in chronic myeloid leukemia (CML) CD34+CD15- cells impact alternative splicing.
• This suggests potential alterations in spliceosome machinery within chronic-phase CML (CP-CML).

Purpose of the Study:

• To investigate the expression of 12 key spliceosome genes in primary CP-CML CD34+ cells at diagnosis.
• To determine if CP-CML CD34+ cells exhibit a distinct splicing signature compared to healthy controls.
• To assess the therapeutic potential of targeting spliceosome function in CML.

Main Methods:

• Analysis of spliceosome gene expression in 15 primary CP-CML CD34+ cells at diagnosis.
• Comparison of splicing profiles between CP-CML CD34+ cells, healthy donor CD34+ cells, and whole CP-CML cells.
• Treatment of CP-CML CD34+ cells with tyrosine kinase inhibitors (TKIs) and/or the spliceosome-targeted drug TG003.

Main Results:

• CP-CML CD34+ cells displayed a unique splicing signature, indicating spliceosome deregulation and intraclonal heterogeneity at diagnosis.
• Three distinct splicing profile types were identified, unrelated to patient characteristics.
• CP-CML CD34+ cells demonstrated dependence on both BCR::ABL and spliceosome function.
• Combined TKI and TG003 treatment showed an additive effect, sparing healthy donor cells.

Conclusions:

• Spliceosome deregulation occurs early in CP-CML.
• The spliceosome represents a potential novel therapeutic target for CML treatment.
• Combination therapy targeting both BCR::ABL and spliceosome may be effective and safe for CML patients.